Nagamatsu et al.

Behavioral and Brain Functions 2011, 7:37

http://www.behavioralandbrainfunctions.com/content/7/1/37

RESEARCH Open Access

Functional neural correlates of reduced

physiological falls risk
Lindsay S Nagamatsu1,2,3,4, Chun Liang Hsu2,4, Todd C Handy1 and Teresa Liu-Ambrose 2,3,4*

Abstract
Background: It is currently unclear whether the function of brain regions associated with executive cognitive
processing are independently associated with reduced physiological falls risk. If these are related, it would suggest
that the development of interventions targeted at improving executive neurocognitive function would be an
effective new approach for reducing physiological falls risk in seniors.
Methods: We performed a secondary analysis of 73 community-dwelling senior women aged 65 to 75 years old
who participated in a 12-month randomized controlled trial of resistance training. Functional MRI data were
acquired while participants performed a modified Eriksen Flanker Task - a task of selective attention and conflict
resolution. Brain volumes were obtained using MRI. Falls risk was assessed using the Physiological Profile
Assessment (PPA).
Results: After accounting for baseline age, experimental group, baseline PPA score, and total baseline white matter
brain volume, baseline activation in the left frontal orbital cortex extending towards the insula was negatively
associated with reduced physiological falls risk over the 12-month period. In contrast, baseline activation in the
paracingulate gyrus extending towards the anterior cingulate gyrus was positively associated with reduced
physiological falls risk.
Conclusions: Baseline activation levels of brain regions underlying response inhibition and selective attention were
independently associated with reduced physiological falls risk. This suggests that falls prevention strategies may be
facilitated by incorporating intervention components - such as aerobic exercise - that are specifically designed to
induce neurocognitive plasticity.
Trial Registration: ClinicalTrials.gov Identifier: NCT00426881

Introduction community-dwelling older adults increase physiological

Falls are a major health care problem for seniors and falls risk [5-8]. Specifically, evidence suggests that
health care systems. They are the third leading cause of reduced executive functions – the ability to concentrate,
chronic disability worldwide [1] and approximately 30% to attend selectively, and to plan and strategize – are
of community-dwellers over the age of 65 years experi- associated with increased falls risk among seniors with-
ence one or more falls every year [2]. Importantly, 5% of out cognitive impairment and dementia [5,6,9-11].
falls result in fracture, with one-third of those being hip Currently, the neural basis for the association between
fractures. reduced executive functions and falls is unclear. Evi-
Key risk factors for falls include reduced physiological dence from neuroimaging studies provides insight to
function, such as impaired balance, [3,4] and cognitive possible underlying mechanisms. Specifically, cerebral
impairment [2]. Recent evidence suggests that even mild white matter lesions (or leukoaraiosis) are associated
reductions in cognitive abilities among otherwise healthy with both reduced executive functions [12] and gait and
balance abnormalities [13-16]. Cerebral white matter
* Correspondence: tlambrose@exchange.ubc.ca lesions may interrupt frontal lobe circuits responsible
2
Centre for Hip Health and Mobility, Vancouver Coastal Research Institute, for normal gait and balance or they may interfere with
University of British Columbia, 7/F 2635 Laurel Street, Vancouver BC, V6H
2K2, Canada long loop reflexes mediated by deep white matter sen-
Full list of author information is available at the end of the article sory and motor tracts [15]. In addition, the
© 2011 Nagamatsu et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative
Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and
reproduction in any medium, provided the original work is properly cited.
Nagamatsu et al. Behavioral and Brain Functions 2011, 7:37
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periventricular and subcortical distribution of white
matter lesions could interrupt the descending motor
fibers arising from medial cortical areas, which are
important for lower extremity motor control [16]. How-
ever, while the results of these neuroimaging studies
contribute to our appreciation of the importance of
brain structure to physiological falls risk, they do not
provide specific guidance for refining or developing falls
prevention strategies because white matter lesions are
not currently modifiable once they present. Studies have
also demonstrated the contribution of brain volume to
physiological falls risk. Specifically, reduced grey matter
volume within sensorimotor and frontal parietal regions
of the brain is associated with both reduced gait speed
and impaired balance [17,18].
Of particular relevance to falls prevention, targeted
exercise training is beneficial for both brain volume, as
assessed by MRI, and brain function, as assessed by
fMRI [19]. What has not been well examined to date is
the contribution of brain function to physiological falls
risk. Using functional magnetic resonance imaging
(fMRI), we previously demonstrated that reduced activ-
ity in the posterior lobe of the right cerebellum during
an executive-challenging cognitive task may be an
underlying neural mechanism for increased falls risk
[20].
To our knowledge, it is currently unknown whether
the function of brain regions responsible for executive
functions are independently associated with reduced
physiological falls risk after accounting for relevant fac-
tors such as baseline age, baseline physiological falls
risk, and baseline brain volume. Yet, such knowledge
would facilitate the development and refinement of tar-
geted interventions to reduce physiological falls risk in
older adults. Thus, we used fMRI to examine the func-
tional neural correlates of executive functioning that are
independently associated with reduced physiological falls
risk among community-dwelling senior women.
Methods
Participants
The sample for this analysis consisted of a subset of 155
women who consented and completed a 12-month ran-
domized controlled trial of exercise (NCT00426881)
that primarily aimed to examine the effect of once-
weekly or twice-weekly resistance training compared
with a twice-weekly balance and tone exercise interven-
tion on cognitive performance of executive functions.
The design and the primary results of the study have
been reported elsewhere [21].
We recruited and randomized 155 senior women who:
1) were aged 65-75 years; 2) were living independently
in their own home; 3) obtained a score ≥ 24 on the
Mini-Mental Status Examination (MMSE) [22]; and 4)
Page 2 of 9
had a visual acuity of at least 20/40, with or without
corrective lenses. We excluded those who: 1) had a diag-
nosed neurodegenerative disease (e.g., AD) and/or
stroke; 2) were taking psychotropic drugs; 3) did not
speak and understand English; 4) had moderate to sig-
nificant impairment with ADLs as determined by inter-
view; 5) were taking cholinesterase inhibitors within the
last 12 months; 6) were taking anti-depressants within
the last six months; or 7) were on oestrogen replace-
ment therapy within the last 12 months.
Ethical approval was obtained from the Vancouver
Coastal Health Research Institute (V06-0326) and the
University of British Columbia’s Clinical Research Ethics
Board (H06-0326). All participants provided written
informed consent.
Randomization
The randomization sequence was generated by http://
www.randomization.com and was concealed until inter-
ventions were assigned. This sequence was held inde-
pendently and remotely by the Research Coordinator.
Participants were enrolled and randomised by the
Research Coordinator to one of three groups: once-
weekly resistance training (1x RT), twice-weekly resis-
tance training (2x RT), or twice-weekly balance and
tone (BAT).
Exercise Intervention
Resistance Training
All classes were 60 minutes in duration. The protocol
for this program was progressive and high-intensity in
nature. Both a Keiser® Pressurized Air system and free
weights were used to provide the training stimulus.
Other key strength exercises included mini-squats, mini-
lunges, and lunge walks.
Balance and Tone
This program consisted of stretching exercises, range of
motion exercises, kegals, balance exercises, and relaxa-
tion techniques. This group served to control for con-
founding variables such as physical training received by
traveling to the training centres, social interaction, and
lifestyle changes secondary to study participation.
Descriptive Variables
Global cognition was assessed using the MMSE [22].
We used the 15-item Geriatric Depression Scale (GDS)
[23] to screen for depression. Functional Comorbidity
Index was calculated to estimate the degree of comor-
bidity associated with physical functioning [24]. This
scale’s score is the total number of comorbidities.
Dependent Variable: Physiological Falls Risk
Physiological falls risk was assessed using the short form
of the physiological profile assessment (PPA; Prince of
Nagamatsu et al. Behavioral and Brain Functions 2011, 7:37
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Wales Medical Research Institute, AUS) to assess phy-
siological falls risk. The PPA measures five domains of
physiological functioning - dominant hand reaction
time, postural sway, contrast sensitivity, proprioception,
and dominant quadriceps strength - and computes a
global falls risk score that has 75% accuracy for predict-
ing falls. Global PPA scores < 0 indicate low falls risk, 0
to 1 indicate mild falls risk, 1 to 2 indicate moderate
falls risk, and scores > 2 indicate high falls risk. We cal-
culated change in physiological falls risk as the differ-
ence score between the baseline global PPA score and
the trial completion PPA score; higher PPA change
scores indicate greater reductions in physiological falls
risk.
Independent Variables of Interest
Brain Structure: Anatomical MRI
Baseline brain volume was measured via high-resolution,
T1-weighted structural MRI images obtained using a
Philips Achieva 3T scanner (TR = 8 ms, TE = 3.7 ms,
bandwidth = 2.26 kHz, voxel size = 1 × 1 × 1 mm).
Brain tissue volume, normalized for subject head size,
was estimated with SIENAX [25], part of FSL (FMRIB’s
Software Library, Version 4.1.4) [26]. SIENAX starts by
extracting brain and skull images from the single whole-
head T1 image [27]. The brain image was then affine-
registered to Montreal Neurological Institute (MNI) 152
space [28,29]. Next, tissue-type segmentation with par-
tial volume estimation was carried out [30] in order to
calculate baseline total volume of brain tissue, total
white matter volume, and total grey matter volume.
Brain Function: Functional MRI
Transverse echo-planar imaging (EPI) images in-plane
with the AC-PC line were acquired using a gradient-
echo pulse sequence and sequential slice acquisition (TR
= 2000 ms, TE = 30 ms, flip angle = 90°, 36 contiguous
slices at 3 mm skip 1 mm, in-plane resolution of 128 ×
128 pixels reconstructed in a FOV of 240 mm). Each
functional run began with four TR’s during which no
data were acquired to allow for steady-state tissue mag-
netization. A total of 148 EPI volumes were collected in
each functional run, and a total of 6 functional runs
were collected for each participant.
During scanning, participants performed a modified
Eriksen flanker task [31] – a task that engages the
executive cognitive processes of selective attention and
conflict resolution (Figure 1). Participants viewed dis-
plays with an arrow at central fixation, flanked by a pair
of arrows on either side. In half the trials, the flanking
arrows pointed in the same direction as the central
arrow cue (e.g., < < < < <; congruent condition), and in
the other half, the flanking arrows pointed in the oppo-
site direction (e.g., > > < > >; incongruent condition).
There were four event types based on whether the
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Figure 1 The Flanker Task. Participants were presented with a
13.5-sec fixation cross, which was followed by a 500 milliseconds
pre-cue that informed participants that the critical stimulus will
appear soon. Finally, an array of five arrows was on the screen.
Participants responded to the orientation of the central arrow cue
by pressing a button with their left hand if the central arrow cue
pointed to the left and with their right hand if the central arrow
cue pointed to the right. During one half of the trials, the flanking
arrows faced in the same direction as the central arrow cue (i.e.,
congruent trials), and during the other half, they pointed in the
opposite direction as the central arrow cue (i.e., incongruent trials).
These stimuli remained on the screen for 2,000 milliseconds. Each
participant underwent six successive five-minute blocks where they
were presented with 17 trials that are first-order counterbalanced
such that consistent and inconsistent trials followed each other
equally [31]. This paradigm is sensitive to age-related decrements in
attention control [48].
central arrow was congruent versus incongruent with
the distracter arrows and whether it pointed to the left
or right. A central fixation cross was presented for 500
milliseconds at the beginning of each trial. The target
stimulus (arrows) was then shown for 2000 millise-
conds. An average of 13500 milliseconds of blank screen
was presented between each trial, jittered between
11500 and 15000 milliseconds. Each participant under-
went six successive five-minute blocks where they were
presented with 17 trials that were first-order counterba-
lanced such that congruent and incongruent trials fol-
lowed each other equally. The participants’ task on each
trial was to signal the direction the central arrow points
via a simple key press. Reaction time was recorded in
milliseconds. At the end of the sessions, a high-resolu-
tion scan allowed each participant’s anatomical and
functional images to be co-registered during data
analysis.
Functional MRI data were processed and analyzed
using SPM2 (http://www.fil.ion.ucl.ac.uk/spm). For each
participant, the EPI images were corrected for motion
using the INRIalign toolbox for SPM2 (http://www-sop.
inria.fr/epidaure/software/INRIAlign/). The resulting
images were spatially-normalized into MNI stereotaxic
coordinates using the EPI template provided with SPM2
[32], and spatially smoothed using an isotropic 8 mm
Nagamatsu et al. Behavioral and Brain Functions 2011, 7:37
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Gaussian kernel. For each participant, the smoothed,
normalized EPI data were analyzed via multiple regres-
sion using a fixed-effects general linear model [33]. In
particular, the event-related responses to the onsets of
the stimuli was examined, with each participant’s model
including four event-related regressors: 1) one for each
combination of target type (i.e., left or right); 2) and dis-
tracter condition (i.e., congruent or incongruent).
Regressors were based on the canonical event-related
hemodynamic response function, temporal derivatives of
the event-related responses were included as additional
regressors, and low-frequency scanner and/or physiolo-
gical noise was modeled via linear, quadratic, and cubic
regressors of non-interest. Group-level analyses were
then based on a random-effects model using one-sample
t-tests, with a threshold of p < 0.05, corrected, and a
minimum extent threshold of 10 contiguous voxels.
Mean beta values reported for clusters identified in the
group-level data were extracted from the SPM2 data
files using custom scripts implemented in MATLAB
(The MATHWORKS Inc., Natick, MA). The group-level
cluster means were calculated by first determining each
participant’s mean beta across all voxels in the given
cluster. All reported voxel coordinates were converted
to Talairaich coordinates [34] using the mni2tal
MATLAB script (http://imaging.mrc-cbu.cam.ac.uk/ima-
ging/MniTalairach). The mean beta values were then
imported to SPSS.
Statistical Analyses
Descriptive data are reported for variables of interest.
Data were analyzed using SPSS Windows Version 18.0
(SPSS Inc., Chicago, IL). The associations between the
variables were determined using the Pearson product
moment coefficient of correlation.
A multiple linear regression model was constructed to
determine the independent association of the neural
correlates of executive functioning, as assessed by fMRI,
with change in physiological falls risk over the 12-
month intervention study, as assessed by PPA. Baseline
age, experimental group, and baseline physiological falls
risk were statistically controlled by entering these three
variables into the regression model first. These indepen-
dent variables were determined from the results of the
Pearson product moment coefficient of correlation ana-
lyses (i.e., baseline PPA score) and based on biological
relevance, such as experimental group and age.
Baseline total brain volume, total white matter
volume, and total grey matter volume were then entered
into regression model and only those that significantly
improved the model were included (i.e., stepwise).
Finally, regions of the brain (i.e., clusters) showing
increases in the hemodynamic response on incongruent
relative to congruent trials of the flanker task were then
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entered into the model using a stepwise approach.
Alpha was set at p ≤ 0.05.
Results
Participants and Variables of Interest
Of the 155 participants who consented and were rando-
mized at baseline, 135 completed the 12-month trial.
Seventy-three of the 135 participants consented and
completed baseline MRI and fMRI scanning.
Table 1 reports the baseline descriptive statistics for
this cohort. The mean baseline PPA score was 0.10,
indicating mild falls risk. At the end of the 12-month
trial, the 73 women demonstrated a mean change of
0.10 in the PPA score. A paired t-test indicated that this
was not a statistically significant change (p = 0.06).
Behavioural performance on the flanker task was cal-
culated as percent increase in reaction time to incongru-
ent stimuli, over and above the average reaction time to
congruent stimuli {[(incongruent reaction time - congru-
ent reaction time)/congruent reaction time] × 100} [31].
The percent increase measure is derived to reflect inter-
ference unbiased by differences in base reaction time.
Only correct responses were included in the analysis.
Mean interference score for BAT, RT1, and RT2 were
16.59 (SD = 13.07), 19.92 (SD = 2.52), and 27.98 (SD =
13.77), respectively.
Consistent with previous studies using the flanker
task, regions showing increases in the hemodynamic
response on incongruent relative to congruent trials
included bilateral inferior and middle frontal gyri, fron-
tal orbital cortex, anterior cingulate cortex (ACC), bilat-
eral precuneus, and the right cerebellum (Figure 2); 14
clusters were identified (Table 2).
Correlation Coefficients
Table 3 reports the bivariate correlation coefficients of
those variables included in the final multiple linear
regression model. Baseline physiological falls risk was
positively and significantly associated with change in
physiological falls risk (p < 0.001). Baseline total brain
volume, total white matter volume, and activation (i.e.,
hemodynamic response) in the left frontal orbital cortex
extending towards the insula (OFC/In) were negatively
and significantly associated with change in physiological
falls risk (p < 0.05). In our bivariate analysis, age, experi-
mental group, and activation in the right paracingulate
gyrus extending towards the anterior cingulate cortex
(PCG/ACC) were not associated with change in physio-
logical falls risk (p > 0.26).
Linear Regression Model
Baseline age, experimental group, and baseline physiologi-
cal falls risk, accounted for 31.9% of the variance in change
in physiological falls risk (Table 3). Adding baseline total
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Table 1 Descriptive statistics for variables of interest (N = 73)

1
Variable BAT 1x RT (n = 28) 2x RT (n = 23) Total (N = 73)
(n = 22) Mean (SD) Mean (SD) Mean (SD)
Mean (SD)
Age (yr) 69.6 (3.1) 69.5 (2.7) 69.1 (3.1) 69.4 (2.9)
Height (cm) 161.5 (6.2) 162.0 (7.5) 162.4 (6.9) 161.9 (6.9)
Weight (kg) 67.1 (10.9) 67.9 (13.6) 68.6 (13.0) 67.9 (12.5)
Education
2
Less than Grade 9 0.0 (0.0) 0.0 (0.0) 0.0 (0.0) 0.0 (0.0)
2
Grade 9 to 12 without Certificate or Diploma 2.0 (9.1) 2.0 (7.1) 0.0 (0.0) 4.0 (5.5)
2
High School Certificate or Diploma 5.0 (22.7) 3.0 (10.7) 5.0 (21.7) 13.0 (17.8)
2
Trades or Professional Certificate or Diploma 3.0 (13.6) 6.0 (21.4) 2.0 (8.7) 11.0 (15.1)
2
University Certificate or Diploma 4.0 (18.2) 5.0 (17.9) 4.0 (17.4) 13.0 (17.8)
2
University Degree 8.0 (36.4) 12.0 (42.9) 12.0 (52.2) 32.0 (43.8)
MMSE Score (max. 30 pts) 28.8 (1.3) 28.6 (1.3) 28.8 (1.0) 28.7 (1.2)
2
Falls in the Last 12 Months (yes/no) 8 (36.4) 7 (25.0) 9 (39.1) 24 (32.9)
Geriatric Depression Scale (/15 pts) 0.7 (2.2) 0.1 (0.8) 0.6 (1.6) 0.5 (1.6)
Functional Comorbidity Index (/18 pts) 2.2 (1.3) 1.9 (1.7) 1.7 (1.5) 1.9 (1.5)
Baseline Physiological Profile Assessment Score 0.10 (0.91) 0.06 (0.89) 0.16 (1.11) 0.10 (0.96)
3
Total Brain Volume 1404767.07 (61101.38) 1392824.85 (74770.29) 1425571.35 (53607.47) 1406741.26 (65216.88)
3
White Matter Volume 673259.09 (37763.87) 668611.61 (33667.89) 680775.90 (30457.92) 673844.81 (33920.23)
3
Gray Matter Volume 731508.20 (30004.57) 731957.93 (35834.91) 746535.05 (35339.77) 736415.19 (34256.96)
Change in Physiological Falls Risk 0.25 (0.97) 0.04 (0.88) 0.34 (0.82) 0.10 (0.96)
1
BAT = Balance and Tone; 1x RT = once-weekly resistance training; 2x RT = twice-weekly resistance training; yr = year; kg = kilogram; MMSE = Mini-Mental State
Examination; sec = seconds.
2
Count = number of “yes” cases within each group. % = percent of “yes” within each group.
3
Brain volume = mm3.

white matter volume resulted in an R-square change of
6.4% and significantly improved the regression model (F
Change = 7.1, p = 0.01). Adding activation in the left
OFC/In to the model resulted in an R-square change of
10.4% and significantly improved the model (F Change =
13.6, p < 0.001). Finally, the inclusion of activation in the
right PCG/ACC resulted in significant R-square change of
4.4% (F Change = 6.6, p = 0.02). The total variance
accounted by the final model was 53.1% (Table 3). Based
on the standardized betas, the left OFC/In was most asso-
ciated with reduced physiological falls risk.
Discussion
Recent evidence strongly suggests that changes in brain
structure with age contribute to problems with mobility
[35-39]. However, less is known about the role of brain
function [20]. To our knowledge, our study is the first
to demonstrate the independent contribution of brain
function to reduced physiological falls risk among com-
munity-dwelling seniors. Specifically, after accounting
for baseline age, experimental group, baseline physiolo-
gical falls risk, and baseline total white matter volume,
activation in the left OFC/In was negatively and inde-
pendently associated with reduced physiological falls
risk in community-dwelling senior women over a 12-
month period. In contrast, activation in the PCG/ACC
was positively and independently associated with
reduced physiological falls risk.
The two regions included in our multiple linear
regression model – the left OFC/In and the right PCG/
ACC – are both part of the neural network associated
with response inhibition and selective attention [40-43].
Response inhibition - the ability to avoid unwanted,
inappropriate responses - is associated with falls in
seniors. For example, Anstey and colleagues [44]
reported that senior fallers (both single and recurrent)
performed significantly worse on a measure of response
inhibition compared to non-fallers. The authors sug-
gested that reduced inhibition results from age-related
declines in functioning of the prefrontal cortex, which
contributes to falls. Given that movement through the
environment requires attending to relevant stimuli and
inhibiting prepotent, yet potentially unsafe, responses, it
is not surprising that brain regions associated with
response inhibition and selective attention are related to
falls risk.
Importantly, we found that activation in the left OFC/In
was negatively associated with reduced physiological falls
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Left OFC/In

Right PCG/ACC

Figure 2 Brain Regions Demonstrating an Increased Hemodynamic Response on Incongruent Relative to Congruent Trials. Data are
group-averaged across all 83 participants and shown on a rendered brain provided with SPM2. Data were thresholded at P < 0.05 (corrected)
and a minimum cluster size of 10 contiguous voxels. The left OFC/In and right PCG/ACC both contributed significantly to our model predicting
change in physiological falls risk.

Table 2 Voxel Cluster Statistics from fMRI

1 2 3
Hemisphere Structure BA K t MNI TAL
X Y Z X Y Z
Right Lateral occipital cortex 19 4247 9.51 28 -78 42 28 -74 42
Right Frontal orbital cortex 47 597 8.18 36 24 -4 36 23 -5
Right Posterior cerebellum 1131 7.95 8 -80 -34 8 -79 -25
Left Lateral occipital cortex 37 626 7.67 -48 -70 -12 -48 -68 -7
Right Paracingulate gyrus 32 1634 7.49 8 20 44 8 21 39
Left Lateral occipital cortex 7 2915 7.43 -22 -72 32 -22 -68 33
Left Middle frontal gyrus 6 1620 7.20 -26 0 50 -26 2 46
Right Middle frontal gyrus 6 631 7.03 26 2 48 26 4 44
Right Inferior frontal gyrus 9 699 6.97 54 14 28 53 15 25
Left Frontal orbital cortex 47 198 6.51 -32 24 -6 -32 23 -6
Left Frontal orbital cortex 47 122 6.19 -46 20 -10 -46 19 -9
Right Supramarginal gyrus 40 82 6.04 28 -68 -28 28 -67 -20
Right Posterior cerebellum 25 5.72 14 -76 -50 14 -76 -38
Right Anterior cerebellum 21 5.69 16 -38 -34 16 -38 -27
Reported coordinates and t values are for the cluster maxima.1 BA = Brodmann’s area. 2
K = # of voxels in the cluster. 3
All p values < 0.05.
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Table 3 Multiple linear regression model summary for improved physiological falls risk
Δ PPA Score (Baseline Score - Trial Completion Score)
Independent Variable r R2 R2 Change Unstandardized B Standardized b p - value
(Standard Error)
Model 1 0.565 0.319 0.319
Group 0.040 0.015 (0.112) 0.013 0.896
Age -0.078 -0.064 (0.031) -0.211 0.043
Baseline PPA Score 0.526** 0.529 (0.094) 0.575 <0.001
Model 2 0.619 0.383 0.064
Group 0.040 0.040 (0.107) 0.035 0.713
Age -0.078 -0.068 (0.030) -0.224 0.026
Baseline PPA Score 0.526** 0.521 (0.090) 0.566 <0.001
White Matter Volume -0.263* -6.670E-6 (0.000) -0.255 0.010
Model 3 0.698 0.487 0.104
Group 0.040 0.034 (0.099) 0.030 0.733
Age -0.078 -0.088 (0.028) -0.287 0.003
Baseline PPA Score 0.526** 0.504 (0.083) 0.548 <0.001
White Matter Volume -0.263* -8.800E-6 (0.000) -0.337 <0.001
Cluster 3 1 -0.258 -0.654 (0.177) -0.339 0.014
Model 4 0.729 0.531 0.044
Group 0.040 0.023 (0.095) 0.021 0.809
Age -0.078 -0.087 (0.027) -0.286 0.002
Baseline PPA Score 0.526** 0.474 (0.081) 0.515 <0.001
White Matter Volume -0.263* -1.000E-5 (0.000) -0.383 <0.001
1
Cluster 3 -0.258* -1.159 (0.266) -0.601 <0.001
2
Cluster 7 -0.055 0.637 (0.271) 0.329 0.016
* P ≤ 0.05
** P ≤ 0.001
1
Cluster 3 is the region of left frontal orbital cortex extending towards the insula.
2
Cluster 7 is the region of right paracingulate gyrus extending towards the anterior cingulate cortex.

risk, whereas activation in the PCG/ACC was positively
associated with reduced physiological falls risk. Increased
activation in the frontal cortex during an executive task,
such as the flanker, is associated with better task perfor-
mance [31]. In contrast, increased activation of the ante-
rior cingulate cortex in older adults is associated with
reduced task performance [31]. In particular, increased
anterior cingulate cortex activation is hypothesized to be
an indicator of greater cognitive effort, such that the ante-
rior cingulate cortex is less efficient at triggering the pre-
frontral system to engage cognitive control [45].
Our volumetric brain results also suggest that total
white matter volume, rather than total grey matter
volume, is associated with change in physiological falls
risk. Previous research suggests that white matter
declines at a faster rate than grey matter in otherwise
healthy older adults [46]. Our results extends this find-
ing by suggesting the loss of total white matter volume
may be an early indicator of increased falls risk among
community-dwelling older adults.
Of particular clinical relevance, the results of our
study suggest that individuals at higher risk for future
falls have greater potential for risk reduction than those
at lower risk for falls. Specifically, our multiple regres-
sion model showed that baseline physiological falls risk
was positively associated with change in physiological
falls risk. Hence, our current study results concurs and
extends that of a previous meta-analysis that concluded
exercise-based falls prevention strategies are most effec-
tive among those at the greatest risk [47]. This suggests
that one intervention strategy for falls prevention may
be to target those who are at greatest risk for falls.
We note that of the independent variables included in
our regression model, baseline activation of the left
OFC/In was most associated with reduced physiological
falls risk. Hence, while many falls interventions focus on
balance training, our study suggests that future falls pre-
vention strategies should potentially incorporate inter-
vention components that induce neurocognitive
plasticity (i.e., changes in brain function). Future work is
needed to establish whether such interventions would
be effective. Current evidence suggests that targeted
aerobic exercise training has specific benefits on neuro-
cognitive plasticity in brain regions that are responsible
for selective attention and response inhibition [31].
Therefore, promoting plasticity in brain regions
Nagamatsu et al. Behavioral and Brain Functions 2011, 7:37
http://www.behavioralandbrainfunctions.com/content/7/1/37
associated with these key executive functions may have
a positive impact on falls prevention.
We acknowledge that our finding that a negative
association between baseline total white matter volume
and change in physiological falls risk is significantly
associated with reduced falls risk contrasts previous
cross-sectional studies on gray matter volume, balance,
and mobility. Specifically, Rosano and colleagues
[17,18] found that reduced gait speed and impaired
balance - key risk factors for falls – were significantly
correlated with reduced grey matter volume within
sensorimotor and frontal parietal regions in the brain.
However, we highlight that our study examined the
independent contribution of baseline volumetric brain
measures to change in falls risk (i.e., longitudinal study
design versus cross-sectional design) and hence our
conclusion that those at the greater risk for future falls
(i.e., smaller baseline total white volume) have greater
potential for falls risk reduction (i.e., greater change in
PPA scores).
We recognize the limitations of our study. A key lim-
itation is that we did not quantify white matter lesions
within total white matter volume. We note that our
study sample consisted exclusively of independent com-
munity-dwelling senior women who were without signif-
icant physical and cognitive impairments and without a
significant history of falls. Thus, the results of our study
may not generalize beyond this population of senior
women and we may have underestimated the contribu-
tion of brain function to change in physiological falls
risk. Future prospective studies are needed to test
whether the present findings also apply to larger, more
heterogeneous populations.
To conclude, the function of brain regions underlying
response inhibition and selective attention was indepen-
dently associated with reduced physiological falls risk.
Hence, future falls prevention strategies should poten-
tially incorporate intervention components, such as
aerobic exercise training, that induce neurocognitive
plasticity in the neural network that supports response
inhibition and selective attention.
Acknowledgements and Funding
The authors would like to thank the Vancouver South Slope YMCA
management and members who enthusiastically supported the study by
allowing access to participants for the training intervention. We thank the
instructors for their commitment to the participants’ health and safety. TLA
is a Michael Smith Foundation for Health Research (MSFHR) Scholar. LSN is a
MSFHR Senior Graduate trainee and a NSERC Doctoral trainee.
This work was supported by the Vancouver Foundation (BCM06-0035), the
Michael Smith Foundation for Health Research Establishment Grant (CI-SCH-
063(05-1)CLIN), and the Canadian Institutes of Health Research (MOB-93373)
to TLA.
Author details
1 Atrophy in the Brain of Older Adults. J Gerontol A Biol Sci Med Sci 2008,
Department of Psychology, University of British Columbia, 2136 West Mall,
Vancouver BC, V6T 1Z4, Canada. 2Centre for Hip Health and Mobility,
Page 8 of 9
Vancouver Coastal Research Institute, University of British Columbia, 7/F 2635
Laurel Street, Vancouver BC, V6H 2K2, Canada. 3Brain Research Centre,
University of British Columbia, 2211 Wesbrook Mall, Vancouver BC, V6T 2B5,
Canada. 4Department of Physical Therapy, University of British Columbia,
#212 2177 Wesbrook Mall, Vancouver BC, V6T 1Z3, Canada.
Authors’ contributions
TLA conceived and designed the study, acquired data, and analyzed and
interpreted the data. LSN and CLH acquired data and participated in the
statistical analysis. TLA, LSN, CLH, and TCH drafted and revised the
manuscript. All authors read and approved the final manuscript.
Declaration of Competing interests
The authors declare that they have no competing interests.
Received: 25 February 2011 Accepted: 16 August 2011
Published: 16 August 2011
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